PXD014794-1

PXD014794 is an original dataset announced via ProteomeXchange.

Title	PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins
Description	Mutations that activate LRRK2 protein kinase cause Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all protein phosphatases revealed that a poorly studied protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins. PPM1H knock out increased endogenous Rab phosphorylation and inhibited Rab dephosphorylation. Overexpression of PPM1H suppressed LRRK2-mediated Rab phosphorylation. PPM1H also efficiently and directly dephosphorylated Rab8A in biochemical studies. A “substrate-trapping” PPM1H mutant (Asp288Ala) binds with high affinity to endogenous, LRRK2-phosphorylated Rab proteins, thereby blocking dephosphorylation seen upon addition of LRRK2 inhibitors. PPM1H is localized to the Golgi and its knockdown suppresses primary cilia formation, similar to pathogenic LRRK2. Thus, PPM1H acts as a key modulator of LRRK2 signaling by controlling dephosphorylation of Rab proteins. PPM1H activity enhancers could offer a new therapeutic approach to prevent or treat Parkinson’s disease
HostingRepository	PRIDE
AnnounceDate	2019-11-06
AnnouncementXML	Submission_2019-11-06_01:54:55.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Raja Sekhar Nirujogi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; phosphorylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion Lumos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-29 01:59:27	ID requested
⏵ 1	2019-11-06 01:54:56	announced

Dataset with its publication pending

submitter keyword: LRRK2, Phosphatase, Parkinson's disease, RAB10

Prof. Dario R. Alessi
contact affiliation	MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom DD1 5EH, UK
contact email	d.r.alessi@dundee.ac.uk
lab head
Raja Sekhar Nirujogi
contact affiliation	MRC Protein Phosphorylation Unit, university of Dundee
contact email	rnirujogi@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014794
     1. Label: PRIDE project
     2. Name: PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins